We will carry out a prospective cohort study of HIV-positive persons recruited from the homeless and marginally housed (H/M) population of San Francisco. We will study the impact of combination antiretroviral therapy with protease inhibitors (PIs) in this cohort. We propose to accrue and follow 375 HIV-positive H/M persons identified in screening of the H/M. This is the REACH cohort. An estimated 160 cohort members will be started on PIs during the proposed study and be followed for at least one year. We will follow the cohort members started on PIs at monthly intervals and will draw blood for virological and genotyping studies. We will determine viral load monthly and presence of resistance mutations to PIs at six-month intervals. We will interview subjects monthly about PI and other therapy, adherence to therapy, predictors of adherence, use of medical care, and HIV risk behavior. The Specific Aims of the study are: 1. We will examine the changing use of combination therapy with PIs in the homeless and marginally housed; 2. We will examine adherence to therapy and determine the predictors of adherence; 3. We will determine the effectiveness of therapy, measured by viral load reduction, in this population, and explore the relationship between adherence to therapy and effectiveness 4. We will determine the incidence of HIV genotypes resistant to PIs in this population and explore the relationship between and the development of resistance. Virological studies will be in the laboratories of Drs. T. Merigan and M. Holodniy at Stanford. We will make laboratory results available to subjects' providers. The REACH cohort will be large enough for analyses of PI use in women, African-Americans, and the "true" homeless. The study is supported by the San Francisco Department of Public Health, the AIDS Research Institute, and the principal providers of health care to the indigent in the city.